Gastric ulcer healing in the rat: kinetics and localisation of de novo procollagen synthesis

Background and aims—To gain further insight into the role of the extracellular matrix during healing of peptic ulcers, sequential changes of procollagen expression were studied over 30 days of ulcer healing.Materials and methods—Procollagens α1(I), α1(III), and α1(IV) RNA and their polypeptides were assessed in acetic acid induced rat gastric ulcers by in situ hybridisation and immunohistochemistry.Results—Three days after ulcer induction, intense hybridisation signals were obtained with all probes, with procollagen α1(I) showing the highest transcript levels. Procollagen gene expression remained elevated up to day 15, but was reduced to initial low levels on day 30. Immunohistochemical staining documented increased deposition of the three procollagen types parallel to their respective transcript levels, again with type I showing the earliest and the most prominent deposits. The highest procollagen transcript levels were found in the intact submucosa surrounding the ulcer margins, followed by the muscularis propria and the serosa, with the lamina propria exhibiting the lowest transcript levels.Conclusion—The procollagens studied are regulated differentially at the transcriptional and post-transcriptional levels. The early onset and long duration of procollagen expression as well as the involvement of all layers of the gastric wall points to their central structural and functional role in gastric ulcer healing.

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Topical transplantation of mesenchymal stem cells accelerates gastric ulcer healing in rats

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00468.2007 ◽

2008 ◽

Vol 294 (3) ◽

pp. G778-G786 ◽

Cited By ~ 32

Author(s):

Yujiro Hayashi ◽

Shingo Tsuji ◽

Masahiko Tsujii ◽

Tsutomu Nishida ◽

Shuji Ishii ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Gastric Ulcer ◽

Growth Factor ◽

Ulcer Healing ◽

Gastric Wall ◽

Female Rats ◽

Male Rats ◽

Gastric Ulcers ◽

Gastric Ulcer Healing

Mesenchymal stem cells (MSCs), a subpopulation of adult somatic stem cells, are an attractive stem cell source in regenerative medicine because of their multipotentiality. We examined the effects of MSC transplantation on gastric ulcer healing. Putative MSCs, isolated from bone marrow aspirates of male rats by dish adherence and expanded in culture, were characterized by flow cytometry and reverse transcription-polymerase chain reaction. Gastric ulcers were induced by serosal application of acetic acid on the anterior wall of the stomach in female rats. Either MSCs (labeled with PKH67; 1×107 cells) or vehicle was injected into the gastric wall surrounding the ulcer. The healing process of the ulcer and the influence of anti-vascular endothelial growth factor (VEGF) antibody were examined. CD29-positive, CD90-positive, CD34-negative, and CD45-negative MSCs expressed mRNAs for VEGF and hepatocyte growth factor (HGF). The MSCs were transplantable to the gastric tissue surrounding the ulcer, where a majority of the engrafted cells were positive for vimentin. The transplantation significantly accelerated gastric ulcer healing compared with controls. The engrafted MSCs also expressed VEGF and HGF. Administration of anti-VEGF neutralizing antibody dose dependently reduced the MSC-induced promotion of ulcer healing. In conclusion, MSC transplantation accelerated gastric ulcer healing, possibly through the induction of angiogenesis in the gastric mucosa via the secretion of VEGF. The beneficial effects of MSCs might be mediated not only by their differentiation into gastric interstitial cells, but also by their ability to supply angiogenic factors.

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Annexin-1 modulates repair of gastric mucosal injury

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00531.2007 ◽

2008 ◽

Vol 294 (3) ◽

pp. G764-G769 ◽

Cited By ~ 38

Author(s):

Gary R. Martin ◽

Mauro Perretti ◽

Roderick J. Flower ◽

John L. Wallace

Keyword(s):

Gastric Ulcer ◽

Ulcer Healing ◽

Mucosal Injury ◽

Formyl Peptide Receptor ◽

Gastric Mucosal Damage ◽

Gastric Ulcers ◽

Wild Type ◽

Gastric Ulcer Healing ◽

Annexin 1 ◽

Deficient Mice

Annexin-1 is a glucocorticoid-inducible protein that plays an important effector role in the resolution of inflammation and has recently been shown to contribute to the resistance of the stomach to injury. Using an integrated genetic and pharmacological approach, we have tested the hypothesis that annexin-1 contributes to the healing of mucosal injury, given that such injury is accompanied by an inflammatory response, which is often associated with an overexpression of annexin-1 expression. Gastric ulcers were induced in mice through serosal application of acetic acid. Annexin-1 expression during the healing of the ulcers was examined. The effects on gastric ulcer healing of treatment with an annexin-1 mimetic (Ac2-26), an antagonist of the annexin-1 receptor (Boc2), or a glucocorticoid (dexamethasone) were examined. Finally, susceptibility to and healing of indomethacin-induced gastric lesions were compared in wild-type and annexin-1-deficient mice. Expression of annexin-1 was significantly increased in the gastric ulcer margin throughout the healing process. Treatment with an annexin-1 mimetic (Ac2-26) significantly enhanced gastric ulcer healing. In contrast, both dexamethasone and an formyl peptide receptor-like-1 (FPRL-1) antagonist impaired the early phase of ulcer healing. Annexin-1-deficient mice exhibited the same susceptibility as wild-type mice to indomethacin-induced gastric damage, but the healing of that damage was impaired in the former. These data support the hypothesis that annexin-1 contributes significantly to the process of healing of gastric mucosal damage.

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Endothelin-1, an ulcer inducer, promotes gastric ulcer healing via mobilizing gastric myofibroblasts and stimulates production of stroma-derived factors

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00462.2005 ◽

2006 ◽

Vol 290 (5) ◽

pp. G1041-G1050 ◽

Cited By ~ 12

Author(s):

Tsutomu Nishida ◽

Shingo Tsuji ◽

Arata Kimura ◽

Masahiko Tsujii ◽

Syuji Ishii ◽

...

Keyword(s):

Gastric Ulcer ◽

Ulcer Healing ◽

Angiogenic Factors ◽

Gastric Epithelium ◽

Gastric Ulcers ◽

Ulcer Formation ◽

Peptic Ulcers ◽

Converting Enzyme ◽

Potent Inducer ◽

Gastric Ulcer Healing

Endothelin (ET)-1 is a potent inducer of peptic ulcers. The roles of ET-1 in ulcer healing, however, have remained unclear, and these were investigated in mice. Gastric ulcers were induced in mice by serosal application of acetic acid. Three days later, mice were given a neutralizing ET-1 antibody or nonimmunized serum. The ulcer size, amount of fibrosis and myofibroblasts, and localization of ET-1 and ETA/B receptors were analyzed. To elucidate the mechanisms underlying the effects of ET-1, we examined the proliferation, migration, and release of growth and angiogenic factors in gastric myofibroblasts with or without ET-1. The expression of prepro-ET-1 (an ET-1 precursor) and ET-converting enzyme-1 was examined in gastric myofibroblasts using RT-PCR. Immunoneutralization of ET-1 delayed gastric ulcer healing. The areas of fibrosis and myofibroblasts were smaller in the anti-ET-1 antibody group than in the control. ET-1 was expressed in the gastric epithelium, myofibroblasts, and other cell types. ETA receptors, but not ETB receptors, were present in myofibroblasts. ET-1 increased proliferation and migration of gastric myofibroblasts. ET-1 stimulated the release of hepatocyte growth factor, VEGF, PGE2, and IL-6 from gastric myofibroblasts. mRNA for prepro-ET-1 and ET-converting enzyme-1 was also expressed. ET-1 promotes the accumulation of gastric myofibroblasts and collagen fibrils at gastric ulcers. ET-1 also stimulates migration and proliferation of gastric myofibroblasts and enhances the release of growth factors, angiogenic factors, and PGE2. Thus ET-1 has important roles not only in ulcer formation but also in ulcer healing via mobilizing myofibroblasts and inducing production of stroma-derived factors.

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Celecoxib appears to significantly delay gastric ulcer healing in patients with complicated gastric ulcers,

Reactions Weekly ◽

10.2165/00128415-200510570-00010 ◽

2005 ◽

Vol &NA; (1057) ◽

pp. 5

Author(s):

&NA;

Keyword(s):

Gastric Ulcer ◽

Ulcer Healing ◽

Gastric Ulcers ◽

Gastric Ulcer Healing

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The Critical Role of Growth Factors in Gastric Ulcer Healing: The Cellular and Molecular Mechanisms and Potential Clinical Implications

Cells ◽

10.3390/cells10081964 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1964

Author(s):

Andrzej S. Tarnawski ◽

Amrita Ahluwalia

Keyword(s):

Cell Proliferation ◽

Gastric Ulcer ◽

Growth Factors ◽

Blood Vessel ◽

Ulcer Healing ◽

Molecular Mechanisms ◽

Tissue Injury ◽

Critical Role ◽

Gastric Wall ◽

Gastric Ulcer Healing

In this article we review the cellular and molecular mechanisms of gastric ulcer healing. A gastric ulcer (GU) is a deep defect in the gastric wall penetrating through the entire mucosa and the muscularis mucosae. GU healing is a regeneration process that encompasses cell dedifferentiation, proliferation, migration, re-epithelialization, formation of granulation tissue, angiogenesis, vasculogenesis, interactions between various cells and the matrix, and tissue remodeling, all resulting in scar formation. All these events are controlled by cytokines and growth factors (e.g., EGF, TGFα, IGF-1, HGF, bFGF, TGFβ, NGF, VEGF, angiopoietins) and transcription factors activated by tissue injury. These growth factors bind to their receptors and trigger cell proliferation, migration, and survival pathways through Ras, MAPK, PI3K/Akt, PLC-γ, and Rho/Rac/actin signaling. The triggers for the activation of these growth factors are tissue injury and hypoxia. EGF, its receptor, IGF-1, HGF, and COX-2 are important for epithelial cell proliferation, migration, re-epithelialization, and gastric gland reconstruction. VEGF, angiopoietins, bFGF, and NGF are crucial for blood vessel regeneration in GU scars. The serum response factor (SRF) is essential for VEGF-induced angiogenesis, re-epithelialization, and blood vessel and muscle restoration. Local therapy with cDNA of human recombinant VEGF165 in combination with angiopoietin1, or with the NGF protein, dramatically accelerates GU healing and improves the quality of mucosal restoration within ulcer scars. The future directions for accelerating and improving healing include local gene and protein therapies with growth factors, their combinations, and the use of stem cells and tissue engineering.

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Bacterial colonization and healing of gastric ulcers: the effects of epidermal growth factor

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2000.278.1.g105 ◽

2000 ◽

Vol 278 (1) ◽

pp. G105-G112 ◽

Cited By ~ 15

Author(s):

Susan N. Elliott ◽

J. L. Wallace ◽

W. McKnight ◽

D. G. Gall ◽

J. A. Hardin ◽

...

Keyword(s):

Gastric Ulcer ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Ulcer Healing ◽

Bacterial Colonization ◽

Neutrophil Infiltration ◽

Gastric Ulcers ◽

Gastric Ulcer Healing ◽

Epidermal Growth

.—Experimental gastric ulcers are rapidly colonized by various bacteria, resulting in significantly impaired healing. Epidermal growth factor (EGF) is capable of preventing bacterial colonization of the healthy intestinal mucosa. In this study, we examined the possibility that EGF accelerates gastric ulcer healing by reducing bacterial colonization of the ulcer. Gastric ulcers were induced by serosal application of acetic acid. The effect of daily administration of EGF on ulcer healing and bacterial colonization was assessed and compared with the effect of daily treatment with broad-spectrum antibiotics. EGF administration reduced colonization levels and accelerated ulcer healing as effectively as the antibiotic treatment. EGF was without effect on acid secretion or neutrophil infiltration into the ulcer. Bacterial growth was not inhibited in the presence of EGF in vitro. These results demonstrate that EGF reduces bacterial colonization during an established infection of a compromised mucosal surface. This effect may contribute to the ability of EGF to accelerate gastric ulcer healing. This effect is acid independent and not due to an anti-inflammatory effect or to direct bactericidal actions.

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Risk stratifying gastric ulcers: development and validation of a scoring system

Frontline Gastroenterology ◽

10.1136/flgastro-2020-101759 ◽

2021 ◽

pp. flgastro-2020-101759

Author(s):

William M Brindle ◽

Rebecca K Grant ◽

Marianne Smith ◽

Meghan Suddaby ◽

Angus Wallace ◽

...

Keyword(s):

Gastric Ulcer ◽

Risk Score ◽

Ulcer Healing ◽

Design Method ◽

External Validation ◽

Area Under The Curve ◽

Gastric Ulcers ◽

Gastric Ulcer Healing ◽

Negative Biopsies

ObjectiveDebate is ongoing regarding the need for universal endoscopic follow-up to ensure gastric ulcer healing. We aimed to assess the value of follow-up oesophago-gastro-duodenoscopies (OGDs) for gastric ulcer healing and stratify patients according to risk of malignancy by developing a risk score.Design/methodAll patients in National Health Service (NHS) Lothian with an index OGD and a diagnosis of gastric ulcer between 1 January 2014 and 31 December 2018 were identified. Data were analysed with logistic regression to identify factors significantly associated with a diagnosis of cancer; a risk score was derived and externally validated.Results778 patients were identified and 60.3% (469/778) of patients had a follow-up OGD. 8.6% (66/778) of patients were diagnosed with cancer. No cases of cancer were found on follow-up OGD of a benign appearing ulcer with negative biopsies. Macroscopic suspicion of malignancy was present at index OGD in 100% (3/3) of those diagnosed with cancer on subsequent OGDs. Older age (p=0.014), increased ulcer size (p<0.001) and non-antral location (p=0.030) were significantly associated with malignancy. A risk score (area under the curve (AUC) 0.868, p<0.001, minimum score=0, maximum score=6) was derived from these variables. 78.0% of patients with malignant ulcers scored ≥3, only 15.8% with benign ulcers scored ≥3 (negative predictive value (NPV) 97.4%). External validation yielded an AUC of 0.862 (p<0.001) and NPV of 98.6%; 84.0% of those with malignant ulcers scored ≥3.ConclusionUlcers with a combination of macroscopically benign appearances, at least six negative biopsies and a low risk score do not necessarily need endoscopic follow-up.

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